Progranulin (PGRN) is a secreted, neuroprotective protein that has been linked to two of the most prevalent neurodegenerative diseases affecting the elderly, frontotemporal dementia (FTD) and Alzheimer's disease (AD). Haploinsufficiency of PGRN has been linked to familial forms of FTD and transgenic mice with PGRN deficiency show neurodegeneration reminiscent of FTD. FTD is the most common dementia among people younger than 60, and is presently untreatable. PGRN may have a broader role in neurodegenerative diseases as PGRN deficiency is linked to increased risk of AD. Because loss of PGRN leads to pathophysiology, a novel disease modifying therapeutic strategy to treat FTD and AD would be to leverage approaches that increase PGRN in the central nervous system (CNS). Since PGRN is a large protein that does not gain access to the CNS, it can't be easily employed as a therapeutic to treat FTD or AD. An alternative approach is to develop small molecule drugs that increase PGRN expression in brain. To begin to identify cellular mechanisms and druggable protein targets that control PGRN expression that could be employed to discover and develop such drugs, we used an unbiased genome-wide siRNA screen that identified a number of potential genetic modifiers that upregulate PGRN levels in neurons. Two genetic modifiers we identified are TRAP1 and FOXO1 and genetically reducing their expression in neurons increases PGRN expression. In studies proposed in this grant, we will test the hypothesis that small molecule drug inhibitors of TRAP1 and FOXO1 that increase PGRN levels in neurons and brain will be neuroprotective and will be therapeutically useful in blocking neurodegeneration in FTD, and by extension, in AD. We will use small molecule inhibitors of TRAP1 and FOXO1 to increase PGRN levels in neurons and test whether they effectively block neurodegeneration and prevent disease in in vitro murine and human neuronal models as well as in vivo in an animal model of FTD. Ultimately, these studies are designed to establish the preclinical efficacy of small molecule TRAP1 and FOXO1 inhibitors to treat FTD. Since the TRAP1 inhibitors have already undergone extensive human clinical evaluation to treat cancer and are well tolerated, demonstrating their efficacy in treating FTD in preclinical studies could support their rapid transition to testing for safety and efficacy in treating FTD patients.